Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease

TY - JOUR

T1 - Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease

AU - Sassi, Celeste

AU - Guerreiro, Rita

AU - Gibbs, Raphael

AU - Ding, Jinhui

AU - Lupton, Michelle K.

AU - Troakes, Claire

AU - Al-Sarraj, Safa

AU - Niblock, Michael

AU - Gallo, Jean Marc

AU - Adnan, Jihad

AU - Killick, Richard

AU - Brown, Kristelle S.

AU - Medway, Christopher

AU - Lord, Jenny

AU - Turton, James

AU - Bras, Jose

AU - Morgan, Kevin

AU - Powell, John F.

AU - Singleton, Andrew

AU - Hardy, John

PY - 2014/12

Y1 - 2014/12

N2 - The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease, and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raises the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes ( APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias.

AB - The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease, and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raises the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes ( APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias.

KW - Alzheimer's disease

KW - APP

KW - Exome sequencing

KW - GRN

KW - MAPT

KW - Neurodegenerative dementia

KW - PRNP

KW - PSEN1

KW - PSEN2

UR - http://www.scopus.com/inward/record.url?scp=84905314759&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2014.06.002

DO - 10.1016/j.neurobiolaging.2014.06.002

M3 - Article

SN - 0197-4580

VL - 35

SP - 2881.e1-2881.e6

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 12

ER -